The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

Abstract

Neuroendocrine neoplasms (NENs) comprise a highly heterogeneous group of tumors arising from the diffuse neuroendocrine system. NENs mainly originate in gastrointestinal, pancreatic, and pulmonary tissues, and despite being rare, show rising incidence. The molecular mechanisms underlying NEN development are still poorly understood, although recent studies are unveiling their genomic, epigenomic and transcriptomic landscapes. RNA was originally considered as an intermediary between DNA and protein. Today, compelling evidence underscores the regulatory relevance of RNA processing, while new RNA molecules emerge with key functional roles in core cell processes. Indeed, correct functioning of the interrelated complementary processes comprising RNA biology, its processing, transport, and surveillance, is essential to ensure adequate cell homeostasis, and its misfunction is related to cancer at multiple levels. This review is focused on the dysregulation of RNA biology in NENs. In particular, we survey alterations in the splicing process and available information implicating the main RNA species and processes in NENs pathology, including their role as biomarkers, and their functionality and targetability. Understanding how NENs precisely (mis)behave requires a profound knowledge at every layer of their heterogeneity, to help improve NEN management. RNA biology provides a wide spectrum of previously unexplored processes and molecules that open new avenues for NEN detection, classification and treatment. The current molecular biology era is rapidly evolving to facilitate a detailed comprehension of cancer biology and is enabling the arrival of personalized, predictive and precision medicine to rare tumors like NENs. Supplementary Information The online version contains supplementary material available at 10.1007/s11154-022-09771-4.

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery

“…The differences observed in the expression pro le of the splicing machinery in pulmonary carcinoid tissue and its surrounding non-neoplastic tissue was expectable, in line to that observed by our group and others in various types of cancer, including pancreatic neuroendocrine tumors (21,23,25,(45)(46)(47)(48). Unlike in other cancers (e.g.…”

“…Notwithstanding this limitation, the differences found do illustrate that tumor tissue displays a distinct splicing machinery landscape. Actually, in keeping with that found in most tumors (except for pituitary adenomas; (21,23,25,(45)(46)(47), the altered components showed higher expression in tumor tissue than in non-tumor tissue, inviting to further explore these molecules as potential diagnostic and prognostic biomarkers. In this regard, selection of the best candidates to be studied in detail can bene t from a two-pronged approach combining objective biocomputational scoring (41) and assessing their association with clinically relevant parameters.…”

“…Indeed, splicing factor overexpression in tumors commonly results in altered splicing patterns, which can be linked to pathological outcomes. Therefore, nding correlations between splicing factor expression and clinical parameters could guide to relevant discoveries (21,22,25,30,45,47). Accordingly, not only SRSF10 expression but that of the other four candidates displayed associations with important diagnostic parameters, such as incidental diagnosis, tumor diameter or detection of malignancy using ne needle aspiration, highlighting their potential as diagnostic biomarkers.…”

“…Alternative splicing dysregulation is a hallmark common to many cancers (17), including neuroendocrine neoplasms (21). Indeed, altered splicing can contribute to tumor initiation, progression and drug response by altering the pattern of splicing of many genes, thereby causing the loss of essential variants for cell homeostasis and appearance of aberrant oncogenic splice variants (17,21,43). A leading cause for such alterations resides in mutations and altered expression in splicing machinery components, which can modify both global patterns of splicing and the set of variants of speci c genes (44).…”

“…Speci cally, 98% of introns are processed by the major spliceosome, while the remaining are spliced by the minor spliceosome, which share most of their components but differ in a limited set of U RNAs and accompanying splicing factors (15). Interestingly, there is now ample evidence that alternative splicing is commonly dysregulated in all tumors and cancers examined (16, 17), including pancreatic NENs and SCLC (18)(19)(20)(21). This dysregulation may lead to the appearance of aberrant splicing variants imparting malignant properties to cancer cells, and has emerged as a transversal hallmark pervading all the other cancer hallmarks (20,(22)(23)(24)(25).…”